Severe Combined Immunodeficiency (SCID)

At a Glance

Severe combined immunodeficiency (SCID) is a primary immunodeficiency caused by a heterogeneous group of genetic conditions that affect the immune system, resulting in severe T- and B-lymphocyte dysfunction.

It is usually detected in neonates as a failure to thrive, leading to severe weight loss and malnutrition. Affected children are often susceptible to life-threatening infections like pneumonia, meningitis, or bloodstream infections. Chronic diarrhea, ear infections, and profuse oral candidiasis commonly occur.

SCID infants can have chronic skin infections caused by Candida, as well as a rash mistakenly diagnosed as eczema. In fact, it is a graft-versus-host disease that develops as a reaction of maternal T-lymphocytes (that have crossed the fetoplacental barrier and entered fetal circulation) against the baby's tissues.

A family history of early infant death (within 2 years of life) that is due to these symptoms should prompt consideration of SCID.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

To confirm the clinical diagnosis of SCID, it is necessary to assess the patient's immune function. The diagnostic test can be performed on venous and cord blood (at birth).

Work-up of SCID should start with a complete blood cell (CBC) count with differential to determine absolute lymphocyte count, and assess lymphoid subpopulations/markers (i.e., percentages and absolute counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and natural killer (NK) cell markers (CD16 and CD56)). In all SCID patients, T-cells are severely affected, whereas the involvement of B- and NK-cells varies based on the particular genetic mutation.

Lymphopenia with an absolute lymphocyte count less than 2500 cells/mL in an infant definitely requires further testing. Full diagnostic assessment should be performed on any infant with severe infection or opportunistic infection. On average, SCID patients have fewer than 1500 lymphocytes/mL.

Total serum immunoglobulin levels of IgG, IgA, IgM, and IgE should be obtained. All immunoglobulin classes are usually, but not always, decreased.

Evaluation of lumphocyte function is key for the diagnosis of the disease. This evaluation s accomplished by assessment of antibodies to standard protein vaccines (e.g., diphtheria and tetanus), isohemagglutinins (IgM against blood group antigens), and mitogen stimulation of lymphocytes. Patients with SCID essentially have no antibody formation and have very poor proliferation of lymphocytes.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Immunoglobulin deficiency might not be recognized until several months after birth. Maternal IgG crosses the placenta into the baby's circulation, so IgG levels in the newborn and young infant can be almost normal, which can affect the evaluation of response to protein vaccines.

What Lab Results Are Absolutely Confirmatory?

SCID is caused by several different genetic defects, and the detection of these mutations by DNA sequencing is the best way to confirm the diagnosis. These tests are now commercially available. DNA sequencing can be done on fetal DNA if the family mutation is known.

The most common form of SCID is X-linked SCID, which is caused by a mutation of the IL-2 receptor gamma. It is possible to perform X-chromosome inactivation studies to determine whether the SCID is X-linked.

Autosomal recessive SCID is caused by mutations of a series of genes (e.g., Janus kinase-3 (JAK-3), adenosine deaminase (ADA), IL-7 receptor alpha chain, CD3 delta or epsilon chain, recombination-activating gene 1 or 2 (RAG1/RAG2), Artemis, CD45). ADA levels can also be determined in lymphocytes, erythrocytes, or fibroblasts.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Screening for the most common forms of SCID, which is now available in some states, is achieved by identifying T-cell receptor excision circles (TRECs), a normal byproduct of T-cell receptor rearrangement. TRECs are barely detectable in SCID infants, whereas they are produced in large numbers in healthy neonates.

It is important to differentiate SCID from other combined immunodeficiencies. Children with combined immune deficiency that is not severe may be difficult to differentiate from children with SCID in the initial evaluations, so confirmatory assays are needed for definitive diagnosis.

Children with complete DiGeorge syndrome have normal B-cell function, but T-cells are absent or nearly absent and, if they are present, they function poorly.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

If it is necessary to exclude HIV infection, order only molecular assays, since IgG antibody assays are of no value because of the presence of maternal IgG antibodies in neonatal circulation.

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